The long-term objective of the proposed research is to relate mechanistic information about the basic properties and activity-dependent plasticity of synaptic connections between identified neurons in the vertebrate central nervous system to the operation of the networks in which they are embedded. The experimental model used in these studies is the goldfish Mauthner (M-) cell and its medullary circuits. This neuron mediates an escape response triggered by sensory stimuli from the eighth nerve, and both the electrotonic and chemical synaptic responses triggered by the eighth nerve input exhibit activity-dependent modifications, namely, long- term potentiation (LTP) and depression (LTD). These synaptic responses are also enhanced by the endogenous modulator dopamine. Intradendritic recordings from the M-cell dendrite will be combined with recordings from single afferents and with nerve stimulation, to test specific hypotheses. about the mechanisms of these modifications. The first aim is to test the hypothesis that the enhancements of synaptic transmission produced by dopamine and LTP share common intracellular regulatory mechanisms, and that dopamine influences the effectiveness of various tetanizing paradigms. This proposal builds on evidence that dopamine acts through a cAMP-dependent pathway. The second aim is to determine the mechanism by which pairing inhibition with a weak tetanus induces LTD. The role of metabotropic glutamate receptors and intracellular Ca++ will be tested. In both aims, the site of the synaptic modification will be determined, with pharmacological methods and postsynaptic injections of compounds that directly interfere with or mimic the effects of the implicated intracellular regulatory pathways. In the third aim, pre- and postsynaptic intracellular recordings will be used to compare the LTP and LTD induced at single connections with modifications in the population responses, and to test the hypothesis that modifications of the strength of single connections depend on their initial efficacy. Particular attention will be paid to the role of silent connections in these phenomena. The fourth aim is concerned with short-term plasticity at these synapses and those between the M-axon and identified cells postsynaptic to it in the brainstem, connections which show a marked depression. Specific molecular probes will be injected presynaptically, to determine the molecular determinants of the probability of release and its plasticity. The data will be analyzed statistically, including the techniques of quantal analysis. The mechanisms of synaptic transmission that will be studied in the proposed research are relevant to numerous health-related issues, such as learning and memory and environmental adaptations of nervous system function. Silent synaptic connections potentially provide the substrate for nervous system adaptation, as a function of experience, during development and in response to traumatic injury or stroke.